1. Field of the Invention
This invention relates to novel fused pyrroleoximes and fused pyrazoleoximes and other such compounds, and more specifically to preferred fused pyrroleoximes and fused pyrazoleoximes that bind with high selectivity and high affinity to the benzodiazepine site of GABAA receptors. This invention also relates to pharmaceutical compositions comprising such compounds and to the use of such compounds in treatment of central nervous system (CNS) diseases.
2. Description of the Related Art
The GABAA receptor superfamily represents one of the classes of receptors through which the major inhibitory neurotransmitter, xcex3-aminobutyric acid, or GABA, acts. Widely, although unequally, distributed through the mammalian brain, GABA mediates many of its actions through a complex of proteins called the GABAA receptor, which causes alteration in chloride conductance and membrane polarization.
A number of cDNAs for GABAA receptor subunits have been characterized. To date at least 6xcex1, 3xcex2, 3xcex3, 1xcex5, 1xcex4 and 2xcfx81 subunits have been identified. It is generally accepted that native GABAA receptors are typically composed of 2xcex1, 2xcex2, and 1xcex3 subunits (Pritchett and Seeburg Science 1989; 245:1389-1392 and Knight et. al., Recept. Channels 1998; 6:1-18). Evidence such as message distribution, genome localization and biochemical study results suggest that the major naturally occurring receptor combinations are xcex11xcex22xcex32, xcex12xcex23xcex32, xcex13xcex23xcex32, and xcex15xcex23xcex32 (Mohler et. al., Neuroch. Res. 1995; 20(5): 631-636).
Benzodiazepines exert their pharmacological actions by interacting with the benzodiazepine binding sites associated with the GABAA receptor. In addition to the benzodiazepine site, the GABAA receptor contains sites of interaction for several other classes of drugs. These include a steroid binding site, a picrotoxin site, and the barbiturate site. The benzodiazepine site of the GABAA receptor is a distinct site on the receptor complex that does not overlap with the site of interaction for GABA or for other classes of drugs that bind to the receptor (see, e.g., Cooper, et al., The Biochemical Basis of Neuropharmacology, 6th ed., 1991, pp. 145-148, Oxford University Press, New York). Early electrophysiological studies indicated that a major action of the benzodiazepines was enhancement of GABAergic inhibition. Compounds that selectively bind to the benzodiazepine site and enhance the ability of GABA to open GABAA receptor channels are agonists of GABA receptors. Other compounds that interact with the same site but negatively modulate the action of GABA are called inverse agonists. Compounds belonging to a third class bind selectively to the benzodiazepine site and yet have little or no effect on GABA activity, but can block the action of GABAA receptor agonists or inverse agonists that act at this site. These compounds are referred to as antagonists.
The important allosteric modulatory effects of drugs acting at the benzodiazepine site were recognized early and the distribution of activities at different receptor subtypes has been an area of intense pharmacological discovery. Agonists that act at the benzodiazepine site are known to exhibit anxiolytic, sedative, and hypnotic effects, while compounds that act as inverse agonists at this site elicit anxiogenic, cognition enhancing, and proconvulsant effects. While benzodiazepines have a long history of pharmaceutical use as anxiolytics, these compounds often exhibit a number of unwanted side effects. These may include cognitive impairment, sedation, ataxia, potentiation of ethanol effects, and a tendency for tolerance and drug dependence.
GABAA selective ligands may also act to potentiate the effects of other CNS active compounds. For example, there is evidence that selective serotonin reuptake inhibitors (SSRIs) may show greater antidepressant activity when used in combination with GABAA selective ligands than when used alone.
This invention provides fused pyrroleoximes and pyrazoleoximes that bind, preferably with both high affinity and high selectivity, to the benzodiazepine site of the GABAA receptor, including human GABAA receptors.
Thus, the invention provides compounds of Formula I, and pharmaceutical compositions comprising compounds of Formula I.
The invention further comprises methods of treating patients suffering from CNS disorders with an effective amount of a compound of the invention. The patient may be a human or other mammal. Treatment of humans, domesticated companion animals (pet) or livestock animals suffering from CNS disorders with an effective amount of a compound of the invention is encompassed by the invention.
In a separate aspect, the invention provides a method of potentiating the actions of other CNS active compounds. This method comprises administering an effective amount of a compound of the invention with another CNS active compound.
Additionally this invention relates to the use of the compounds of the invention as probes for the localization of GABAA receptors in tissue sections.
Accordingly, a broad aspect of the invention is directed to compounds of Formula I 
and the pharmaceutically acceptable salts thereof, wherein:
R is hydroxy, hydrocarbyl or xe2x80x94O-hydrocarbyl, where each hydrocarbyl is optionally substituted with oxo, haloalkyl, haloalkoxy, halogen, cyano, hydroxy, alkyl, nitro, azido, alkanoyl, carboxamido, alkoxy, aryloxy, alkylthio, alkylsulfinyl, alkylsulfonyl, amino, mono or dialkylamino, aryl, arylalkyl, arylalkoxy, heteroaryl or heterocycloalkyl; or
R is xe2x80x94O-aryl, aryl, xe2x80x94O-heteroaryl, or heteroaryl, each of which is optionally substituted with halogen, cyano, hydroxyl, nitro, azido, alkanoyl, carboxamido, hydrocarbyl, xe2x80x94O-hydrocarbyl, aryloxy, haloalkyl, haloalkoxy, hydrocarbylthio hydrocarbylsulfinyl, hydrocarbylsulfonyl, amino, mono or dihydrocarbylamino, aryl, arylhydrocarbyl, arylalkoxy, heteroaryl or heterocycloalkyl;
wherein each hydrocarbyl is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of oxo, halogen, cyano, nitro, haloalkyl, haloalkoxy, hydroxy, amino, alkyl substituted with 0-2 RA, alkoxy substituted with 0-2 RA, xe2x80x94NH(alkyl) substituted with 0-2 RA, xe2x80x94N(alkyl)(alkyl) where each alkyl is independently substituted with 0-2 RA, phenyl substituted with 0-3 RA, xe2x80x94XRB, and RC; wherein
RA is independently selected at each occurrence from the group consisting of halogen, hydroxy, alkyl, alkoxy, xe2x80x94NH(alkyl), xe2x80x94N(alkyl)(alkyl), heterocycloalkyl, xe2x80x94S(O)m(alkyl), where m is 0, 1, or 2, haloalkyl, haloalkoxy, xe2x80x94CO(alkyl), xe2x80x94CONH(alkyl), xe2x80x94CON (alkyl) (alkyl), xe2x80x94XRB, and Y;
X is independently selected at each occurrence from the group consisting of xe2x80x94CH2xe2x80x94, xe2x80x94CHRCxe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94S(O)gxe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94NRCxe2x80x94, xe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94C(xe2x95x90O)Oxe2x80x94, xe2x80x94C(xe2x95x90O)NHxe2x80x94, xe2x80x94C(xe2x95x90O)NRCxe2x80x94, xe2x80x94S(O)gNHxe2x80x94, xe2x80x94S(O)gNRCxe2x80x94, NHC(xe2x95x90O)xe2x80x94, xe2x80x94NRCC(xe2x95x90O)xe2x80x94, xe2x80x94NHS(O)gxe2x80x94, and xe2x80x94NRCS(O)gxe2x80x94; where g is 0, 1, or 2;
RB and RC are independently hydrocarbyl which may be further substituted with one or more substituents independently selected from oxo, hydroxy, halogen, amino, xe2x80x94NH(alkyl), xe2x80x94N(alkyl)(alkyl), cyano, nitro, haloalkyl, haloalkoxy, xe2x80x94O(alkyl), xe2x80x94NHC(O)(alkyl), xe2x80x94N(alkyl)C(O)(alkyl), xe2x80x94NHS(O)m(alkyl), xe2x80x94S(O)m(alkyl), xe2x80x94S(O)mNH(alkyl), and xe2x80x94S(O)mN(alkyl)(alkyl); where each m is 0, 1, or 2;
Y is independently selected at each occurrence from 5- to 8-membered carbocycles or heterocycles, which are saturated, partially unsaturated, or aromatic and contain zero, one or two hetero atoms selected from N, O, and S, and which may be further substituted with one or more substituents independently selected from the group consisting of halogen, oxo, hydroxy, amino, mono- or di(C1-C6)alkylamino, nitro, cyano, C1-C6 alkyl, C1-C6 alkoxy, and xe2x80x94SOa(alkyl); where a is 0, 1, or 2;
R1 and R2 are independently selected at each occurrence from hydrogen, halogen, hydroxy, hydrocarbyl, xe2x80x94O-hydrocarbyl, alkoxy, haloalkyl, haloalkoxy, nitro, cyano, amino, mono or dihydrocarbylamino;
n is 0, 1, or 2;
A is N or CR3, wherein R3 is hydrogen or hydrocarbyl;
Ar is aryl or heteroaryl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of oxo, haloalkyl, haloalkoxy, halogen, cyano, hydroxy, nitro, azido, alkanoyl, carboxamido, hydrocarbyl substituted with 0-2 RA, xe2x80x94O-hydrocarbyl substituted with 0-2 RA, aryloxy, alkylthio hydrocarbylsulfinyl, hydrocarbylsulfonyl, amino, xe2x80x94NH(hydrocarbyl) substituted with 0-2 RA, xe2x80x94N(hydrocarbyl)(hydrocarbyl) wherein each hydrocarbyl is substituted with 0-2 RA, aryl, arylhydrocarbyl, arylalkoxy, heteroaryl and heterocycloalkyl; and
R40 is hydrogen, alkyl, arylalkyl or arylalkanoyl.
The invention also provides intermediates and methods of making the compounds of the invention.
In a specific aspect, the invention provides compounds of Formula I where A is nitrogen and n is 0. In another specific aspect, the invention provides compounds of Formula I where A is CR3, where R3 is defined above, and n is 0.
In another specific aspect, the invention provides compounds of Formula I where A is nitrogen and n is 1. In yet another specific aspect, the invention provides compounds of Formula I where A is CR3, where R3 is defined above, and n is 1.
In a yet further specific aspect, the invention provides compounds of Formula I where A is nitrogen and n is 2. In yet another specific aspect, the invention provides compounds of Formula I where A is CR3, where R3 is defined above, and n is 2.
More preferably the invention relates to compounds of Formula I and the pharmaceutically acceptable salts thereof, where
R is hydroxy, alkyl, cycloalkyl, alkoxy, or cycloalkyloxy each of which is optionally substituted with oxo, haloalkyl, haloalkoxy halogen, cyano, hydroxy, alkyl, nitro, azido, alkanoyl, carboxamido, alkoxy, aryloxy, alkylthio, alkylsulfinyl, alkylsulfonyl, amino, mono or dialkylamino, aryl, arylalkyl, arylalkoxy, heteroaryl or heterocycloalkyl; or
R is phenyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridizinyl, benzimidazolyl, naphthyl, indolyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzo[b]thiophenyl, benz[d]isoxazolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, or quinoxalinyl, each of which is optionally mono-, di-, or trisubstituted with substituents independently chosen from halogen, cyano, nitro, haloalkyl, haloalkoxy, hydroxy, amino, alkyl substituted with 0-2 RA, alkoxy substituted with 0-2 RA, xe2x80x94NH(alkyl) substituted with 0-2 RA, xe2x80x94N(alkyl)(alkyl) where each alkyl is independently substituted with 0-2 RA, phenyl substituted with 0-3 RA, xe2x80x94XRB, and RC;
Ar is phenyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridizinyl, benzimidazolyl, naphthyl, indolyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzo[b]thiophenyl, benz[d]isoxazolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, or quinoxalinyl, each of which is optionally mono-, di-, or trisubstituted with substitutents independently chosen from oxo, halogen, cyano, nitro, haloalkyl, haloalkoxy, hydroxy, amino, alkyl substituted with 0-2 RA, alkoxy substituted with 0-2 RA, xe2x80x94NH(alkyl) substituted with 0-2 RA, xe2x80x94N(alkyl)(alkyl) where each alkyl is independently substituted with 0-2 RA, xe2x80x94XRB, and RC;
RA is independently selected at each occurrence from the group consisting of halogen, hydroxy, alkyl, alkoxy, xe2x80x94NH(alkyl), xe2x80x94N(alkyl)(alkyl), morpholinyl, pyrrolidinyl, piperidinyl, thiomorpholinyl, piperazinyl, xe2x80x94S(O)m(alkyl), where m is 0, 1, or 2, haloalkyl, haloalkoxyoxy, xe2x80x94CO(alkyl), CONH(alkyl), CON(alkyl)(alkyl), xe2x80x94XRB, and Y, where X, Y, RA,RB, and RC are as defined with respect to Formula I.
Such compounds are referred to hereinafter as compounds of Formula Ia.
Preferred compounds of Formula Ia are those compounds where each alkyl is C1-C6 alkyl and each alkoxy is C1-C6 alkoxy. Such compounds are referred to hereinafter as compounds of Formula Ib.
Preferred compounds of Formula I include those where
Ar is phenyl, pyridyl, pyrimidinyl, pyrazolyl, or pyridizinyl, each of which is unsubstituted or substituted with up to three groups selected from halogen, cyano, nitro, C1-C6haloalkyl, C1-C6haloalkoxy, hydroxy, amino, and C1-C6alkyl substituted with 0-2 RA, C1-C6alkoxy substituted with 0-2 RA, xe2x80x94NH(C1-C6alkyl) substituted with 0-2 RA, and xe2x80x94N(C1-C6alkyl)(C1-C6alkyl) where each alkyl is independently substituted with 0-2 RA, xe2x80x94XRB, and RC;
RA is independently selected at each occurrence the group consisting of halogen, hydroxy, C1-C6alkyl, C1-C6alkoxy, xe2x80x94NH(C1-C6alkyl), xe2x80x94N(C1-C6alkyl)(C1-C6alkyl), C1-C6haloalkyl, C1-C6haloalkoxy, xe2x80x94XRB and Y;
X is independently selected at each occurrence from the group consisting of xe2x80x94CH2xe2x80x94, xe2x80x94CHRCxe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94NRCxe2x80x94, and xe2x80x94C(xe2x95x90O)xe2x80x94;
RB and RC are independently C1-C6 alkyl, C3-C7cycloalkyl, or C3-C7cycloalkyl(C1-C6)alkyl, each of is optionally substituted with one or more substituents independently selected from oxo, hydroxy, halogen, amino, cyano, nitro, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkyl, C1-C6 alkoxy, mono- or di(C1-C6)alkylamino, xe2x80x94NHC(O)(C1-6 alkyl), and xe2x80x94N(C1-C6 alkyl)C(O)(C1-C6alkyl), where m is 0, 1, or 2; and
Y is morpholinyl, homopiperazinyl, piperazinyl, homo piperidinyl, piperidinyl, tetrahydropyridyl, imidazolyl, imidazolinyl, or imidazolidinyl.
More preferred compounds and pharmaceutically acceptable salts of Formula I include those where
R is hydroxy, C1-C6alkyl, cycloalkyl, C1-C6alkoxy, or cycloalkyloxy each of which is optionally substituted with oxo, C1-C6haloalkyl, C1-C6haloalkoxy halogen, cyano, hydroxy, C1-C6alkyl, nitro, azido, C1-C6alkanoyl, carboxamido, C1-C6alkoxy, aryloxy, C1-C6alkylthio, C1-C6alkylsulfinyl, C1-C6alkylsulfonyl, amino, mono or di(C1-C6)alkylamino, aryl, aryl(C1-C4)alkyl, aryl(C1-C4)alkoxy, heteroaryl or heterocycloalkyl; or
R is phenyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridizinyl, benzimidazolyl, naphthyl, indolyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzo[b]thiophenyl, benz[d]isoxazolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, or quinoxalinyl, each of which is optionally mono-, di-, or trisubstituted with substituents independently chosen from halogen, cyano, nitro, C1-C6haloalkyl, C1-C6haloalkoxy, hydroxy, amino, C1-C6alkyl substituted with 0-2 RA, C1-C6alkoxy substituted with 0-2 RA, xe2x80x94NH(C1-C6alkyl) substituted with 0-2 RA, xe2x80x94N(C1-C6alkyl)(C1-C6alkyl) where each alkyl is independently substituted with 0-2 RA, phenyl substituted with 0-3 RA, xe2x80x94XRB, and RC;
R1 and R2 are independently selected at each occurrence from hydrogen, halogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, C1-C6haloalkyl, C1-C6haloalkoxy, nitro, cyano, amino, mono- or di-(C1-C6)alkylamino;
Ar is phenyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridizinyl, benzimidazolyl, naphthyl, indolyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzo[b]thiophenyl, benz[d]isoxazolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, or quinoxalinyl, each of which is optionally mono-, di-, or trisubstituted with substitutents independently chosen from oxo, halogen, cyano, nitro, C1-C6haloalkyl, C1-C6haloalkoxy, hydroxy, amino, C1-C6alkyl substituted with 0-2 RA, C1-C6alkoxy substituted with 0-2 RA, xe2x80x94NH(C1-C6alkyl) substituted with 0-2 RA, xe2x80x94N(C1-C6alkyl)(C1-C6alkyl) where each C1-C6alkyl is independently substituted with 0-2 RA, xe2x80x94XRB, and RC;
RA is independently selected at each occurrence from the group consisting of halogen, hydroxy, C1-C6alkyl, C1-C6alkoxy, xe2x80x94NH(C1-C6alkyl), xe2x80x94N(C1-C6alkyl)(C1-C6alkyl), morpholinyl, pyrrolidinyl, piperidinyl, thiomorpholinyl, piperazinyl, xe2x80x94S(O)m(alkyl), where m is 0, 1, or 2, C1-C6haloalkyl, C1-C6haloalkoxy, xe2x80x94CO(C1-C6alkyl), CONH(C1-C6alkyl), CON(C1-C6alkyl)(C1-C6alkyl), xe2x80x94XRB, and Y; and
RB and RC are independently C1-C6hydrocarbyl which may be further substituted with one or more substituents independently selected from oxo, hydroxy, halogen, amino, xe2x80x94NH (C1-C6alkyl), xe2x80x94N(C1-C6alkyl)(C1-C6alkyl), cyano, nitro, C1-C6 haloalkyl, C1-C6haloalkoxy, xe2x80x94O(C1-C6alkyl), xe2x80x94NHC(O)(C1-C6alkyl), xe2x80x94N(C1-C6alkyl)C(O)(C1-C6alkyl), xe2x80x94NHS(O)m(C1-C6alkyl), xe2x80x94S(O)m(C1-C6alkyl), xe2x80x94S(O)mNH(C1-C6alkyl), and xe2x80x94S(O)mN(C1-C6alkyl)(C1-C6alkyl); where each m is 0, 1, or 2.
Particularly, the invention includes compounds where A is nitrogen, i.e. compounds of Formula II (below) 
and the pharmaceutically acceptable salts thereof, wherein n, R, R1, R2 and Ar are as defined for Formula I.
Preferred compounds of Formula II are compounds wherein n is 1 (hereinafter compounds of Formula IIa).
Particularly preferred compounds of Formula IIa are those compounds wherein
R1 and R2 are C1-C6 alkyl, C1-C6 alkoxy, hydrogen, cyano, amino, amino(C1-C6)alkyl, halo(C1-C6)alkyl, or halo(C1-C6)alkoxy; and
Ar is phenyl, pyridyl, pyrimidinyl, pyrazolyl, or pyridizinyl, each of which is unsubstituted or substituted with up to three groups selected from halogen, cyano, nitro, C1-C6haloalkyl, C1-C6haloalkoxy, hydroxy, amino, and C1-C6alkyl substituted with 0-2 RA, C1-C6alkoxy substituted with 0-2 RA, xe2x80x94NH(C1-C6alkyl) substituted with 0-2 RA, and xe2x80x94N(C1-C6alkyl)(C1-C6alkyl) where each alkyl is independently substituted with 0-2 RA, -xe2x80x94XRB, and RC;
RA is independently selected at each occurrence the group consisting of halogen, hydroxy, C1-C6alkyl, C1-C6alkoxy, xe2x80x94NH (C1-C6alkyl), xe2x80x94N(C1-C6alkyl)(C1-C6alkyl), C1-C6haloalkyl, C1-C6haloalkoxy, xe2x80x94XRB and Y;
X is independently selected at each occurrence from the group consisting of xe2x80x94CH2xe2x80x94, xe2x80x94CHRCxe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94NRCxe2x80x94, and xe2x80x94C(xe2x95x90O)xe2x80x94;
RB and RC are independently C1-C6 alkyl, C3-C7cycloalkyl, or C3-C7cycloalkyl (C1-C6)alkyl, each of is optionally substituted with one or more substituents independently selected from oxo, hydroxy, halogen, amino, cyano, nitro, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkyl, C1-C6 alkoxy, mono- or di(C1-C6)alkylamino, xe2x80x94NHC (O)(C1-C6 alkyl), and xe2x80x94N(C1-C6 alkyl)C(O)(C1-C6 alkyl), where m is 0, 1, or 2; and
Y is morpholinyl, homopiperazinyl, piperazinyl, homo piperidinyl, piperidinyl, tetrahydropyridyl, imidazolyl, imidazolinyl, or imidazolidinyl.
Such compounds are referred to hereinafter as compounds of Formula IIc. Preferred compounds of Formula IIc are those compounds wherein R1 and R2 are defined as for Formula IIc and
R is C1-C6 alkyl or xe2x80x94Oxe2x80x94C1-C6alkyl, wherein C1-C6 alkyl is straight or branched and may contain double or triple bonds; or
R is C3-C7 cycloalkyl or xe2x80x94Oxe2x80x94C3-C7alkyl or
R is phenyl or pyridyl, wherein each phenyl or pyridyl is unsubstituted or mono-, di-, or trisubstituted with halogen, cyano, nitro, halo(C1-C6)alkyl, halo(C1-C6)alkoxy, hydroxy, amino, C1-C6alkyl substituted with 0-2 RA, C1-C6alkoxy substituted with 0-2 RA, xe2x80x94NH(C1-6 alkyl) substituted with 0-2 RA, xe2x80x94N(C1-C6alkyl)(C1-C6alkyl) where each C1-C6alkyl is independently substituted with 0-2 RA, phenyl substituted with 0-3 RA, xe2x80x94XRB, and RC, wherein X, RA, RB, and RC are defined as for Formula I.
Such compounds are referred to hereinafter as compounds of Formula IId. Also preferred are compounds of Formula II, IIa, IIc, and IId wherein R1 and R2 are independently selected at each occurrence from hydrogen, halogen, methyl and ethyl.
As noted above, preferred compounds of Formula II include those where n is 1. Other preferred compounds of Formula II are those where n is 0, or where n is 2.
Other preferred compounds and pharmaceutically acceptable salts of Formula I are those wherein:
Ar is phenyl, pyridyl, or pyridizinyl each of which is optionally mono-, di-, or tri-substituted with substituents independently chosen from
halogen, C1-C6 alkyl, C1-C6 alkoxy, amino, mono- or di(C1-C6)alkylamino, C1-C6alkoxy(C1-C6)alkoxy, C1-C6 alkylamino(C1-C6)alkoxy, amino (C1-C6)alkoxy, di (C1-C6)alkylamino(C1-C6)alkoxy, C1-C6alkoxy (C1-C6)alkylamino,
alkyl substituted with morpholinyl, homopiperazinyl, piperazinyl, homopiperidinyl, piperidinyl, tetrahydropyridyl, imidazolyl, imidazolinyl, or imidazolidinyl, and
C1-C6 alkoxy substituted with morpholinyl, homopiperazinyl, piperazinyl, homo piperidinyl, piperidinyl, tetrahydropyridyl, imidazolyl, imidazolinyl, and imidazolidinyl.
The invention also includes compounds and pharmaceutically acceptable salts of Formula II wherein Ar is phenyl, pyridyl, or pyridinzyl, each of which is substituted with one of
i) halogen, C1-C6 alkyl, C1-C6 alkoxy, mono- or di-(C1-C6)alkylamino, C1-C6alkoxy(C1-C6)alkoxy, mono or di-(C1-C6)alkylamino(C1-C6)alkoxy, or
ii) C1-C6 alkoxy substituted with morpholinyl, homopiperazinyl, piperazinyl, homopiperidinyl, piperidinyl, tetrahydropyridyl, imidazolyl, imidazolinyl, or imidazolidinyl and
Ar is optionally further substituted with one or two substitutuents independently chosen from halogen, C1-C4 alkyl, C1-C4 alkoxy, amino, C1-C6 alkylamino, C1-C3 alkoxy(C1-C3)alkoxy, C1-C3 alkylamino(C1-C3)alkoxy, amino(C1-C3)alkoxy, C1-C3 alkylamino(C1-C3)alkoxy, and C1-C6 alkoxy(C1-C6)alkylamino.
Particularly preferred definitions for the variables R1 and R2 of Formula II include hydrogen, C1-C2 alkyl, C1-C2 alkoxy, cyano, amino, and halogen. It is also preferred that not more than three of R1 and R2 are other than hydrogen. More preferred compounds and salts of Formula II are those wherein one, two, or three of R1 and R2 are independently chosen from hydrogen, halogen, methyl and ethyl, and the remaining R1 and R2 substituents are hydrogen.
The invention is further directed to compounds and salts of Formula II, wherein
R is C1-C6alkyl, C1-C6alkoxy, phenyl(C1-C6)alkyl, pyridyl(C1-C6)alkyl, phenyl or pyridyl, wherein each phenyl or pyridyl is unsubstituted or mono-, di-, or trisubstituted with halogen, cyano, nitro, halo(C1-C6)alkyl, halo(C1-C6)alkoxy, hydroxy, amino, C1-C6alkyl substituted with 0-2 RA, C1-C6alkoxy substituted with 0-2 RA, xe2x80x94NH(C1-C6 alkyl) substituted with 0-2 RA, xe2x80x94N(C1-C6alkyl)(C1-C6alkyl) where each C1-C6alkyl is independently substituted with 0-2 RA, phenyl substituted with 0-3 RA, xe2x80x94XRB, and RC.
Furthermore the invention is directed to compounds and pharmaceutically acceptable salts of Formula II wherein
R is C1-6 alkyl, C1-C6 alkoxy, or
phenyl(C1-C6)alkyl, pyridyl(C1-C6)alkyl, phenyl or pyridyl, where the aromatic portion of each is unsubstituted or mono-, di-, or trisubstituted with halogen, cyano, nitro, C1-C6haloalkyl, C1-C6haloalkoxy, hydroxy, amino, C1-C6 alkoxy, or C1-C6 alkyl.
The invention is also directed to compounds and pharmaceutically acceptable salts of Formula II wherein
R is C1-C4alkyl, C1-C4alkoxy, or phenyl, where the phenyl is mono- or di-substituted with substituents independently chosen from halogen, cyano, nitro, C1-C6haloalkyl, C1-C6haloalkoxy, hydroxy, amino, C1-C6 alkoxy, C1-6 alkyl, amino(C1-C6)alkyl, mono- or di(C1-C6)alkylamino(C1-C6)alkyl, and mono- or di(C1-C6)alkylamino(C1-C6)alkoxy.
Particularly included in the invention are compounds and pharmaceutically acceptable salts of Formula II wherein:
Ar is phenyl, pyridyl, pyrimidinyl, pyrazolyl, or pyridizinyl, each of which is unsubstituted or substituted with up to three groups independently selected from halogen, cyano, nitro, C1-C6haloalkyl, C1-C6haloalkoxy, hydroxy, amino, and C1-C6alkyl substituted with 0-2 RA, C1-C6alkoxy substituted with 0-2 RA, xe2x80x94NH(C1-C6alkyl) substituted with 0-2 RA, xe2x80x94N(C1-C6alkyl)(C1-C6alkyl) where each alkyl is independently substituted with 0-2 RA, xe2x80x94XRB, and RC;
RA is independently selected at each occurrence the group consisting of halogen, hydroxy, C1-C6alkyl, C1-C6alkoxy, xe2x80x94NH(C1-C6alkyl), xe2x80x94N(C1-C6alkyl)(C1-C6alkyl) C1-C6haloalkyl, C1-C6haloalkoxy, CO(C1-C6alkyl), CONH(C1-C6alkyl), CON(C1-C6alkyl)(C1-C6alkyl), xe2x80x94XRB and Y;
X is independently selected at each occurrence from the group consisting of xe2x80x94CH2xe2x80x94, xe2x80x94CHRCxe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94S(O)gxe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94NRCxe2x80x94, xe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94C(xe2x95x90O)Oxe2x80x94, xe2x80x94C(xe2x95x90O)NHxe2x80x94, xe2x80x94C(xe2x95x90O)NRCxe2x80x94, xe2x80x94S(O)gNHxe2x80x94, xe2x80x94S(O)gNRCxe2x80x94, NHC(xe2x95x90O)xe2x80x94, xe2x80x94NRCC(xe2x95x90O)xe2x80x94, xe2x80x94NHS(O)gxe2x80x94, and xe2x80x94NRCS(O)gxe2x80x94; where g is 0, 1, or 2; RB and RC are independently alkyl groups which may be further substituted with one or more substituent(s) selected from oxo, hydroxy, halogen, amino, cyano, nitro, C1-C6haloalkyl, C1-C6haloalkoxy, xe2x80x94O(C1-C6alkyl), xe2x80x94NH(C1-6 alkyl), xe2x80x94N(C1-C6alkyl)(C1-6 alkyl), xe2x80x94NHC(O)(C1-C6alkyl), xe2x80x94N(alkyl)C(O)(C1-C6alkyl), xe2x80x94NHS(O)m(C1-C6alkyl), xe2x80x94S(O)m(C1-C6alkyl), xe2x80x94S(O)mNH(C1-C6alkyl), and xe2x80x94S(O)mN (C1-C6alkyl)(C1-C6alkyl); where m is 0, 1, or 2; and
Y is morpholinyl, homopiperazinyl, piperazinyl, homo piperidinyl, piperidinyl, tetrahydropyridyl, imidazolyl, imidazolinyl, or imidazolidinyl, each of which is unsubstituted or further substituted with one or more substituents independently chosen from halogen, oxo, hydroxy, amino, mono- or di(C1-C6)alkylamino, nitro, cyano, C1-C6 alkyl, C1-C6 alkoxy.
Particularly preferred compounds and pharmaceutically acceptable salts of Formula II are those
Where Ar is phenyl, 2-pyridyl, 3-pyridyl or pyridinzyl, each of which is substituted at the position para to the point of attachment of Ar with one of:
i) halogen, C1-C6 alkyl, C1-C6 alkoxy, mono- or di-(C1-C6)alkylamino, C1-C6alkoxy(C1-C6)alkoxy, mono or di-(C1-C6)alkylamino(C1-C6)alkoxy, or
ii) C1-C6 alkoxy substituted with morpholinyl, homopiperazinyl, piperazinyl, homopiperidinyl, piperidinyl, tetrahydropyridyl, imidazolyl, imidazolinyl, or imidazolidinyl; and
Ar is optionally further substituted with one or two substituents independently chosen from:
halogen, C1-C4 alkyl, C1-C4 alkoxy, amino, C1-C6 alkylamino, C1-C3 alkoxy(C1-C3)alkoxy, C1-C3 alkylamino(C1-C3)alkoxy, amino(C1-C3)alkoxy, C1-C3 alkylamino(C1-C3)alkoxy, and C1-C6 alkoxy(C1-C6)alkylamino;
R is C1-C4 alkoxy; and
one, two, or three of R1 and R2 are independently hydrogen, halogen, methyl or ethyl, and the remaining R1 and R2 substituents are hydrogen.
Other particularly preferred compounds and pharmaceutically acceptable salts of Formula II are those wherein Ar is phenyl or 2-pyridyl, each of which is substituted at the position meta to the point of attachment of Ar with one of
i) halogen, C1-C6 alkyl, C1-C6 alkoxy, mono- or di-(C1-C6)alkylamino, C1-C6alkoxy(C1-C6)alkoxy, mono or di-(C1-C6)alkylamino(C1-C6)alkoxy, or
ii) C1-C6 alkoxy substituted with morpholinyl, homopiperazinyl, piperazinyl, homopiperidinyl, piperidinyl, tetrahydropyridyl, imidazolyl, imidazolinyl, or imidazolidinyl; and
Ar is optionally further substituted with one or two substituents independently chosen from:
halogen, C1-C4 alkyl, C1-C4 alkoxy, amino, C1-C6 alkylamino, C1-C3 alkoxy(C1-C3)alkoxy, C1-C3 alkylamino(C1-C3)alkoxy, amino(C1-C3)alkoxy, C1-C3 alkylamino(C1-C3)alkoxy, and C1-C6 alkoxy (C1-C6)alkylamino;
R is C1-C4 alkoxy; and
one, two, or three of R1 and R2 are independently hydrogen, halogen, methyl or ethyl, and the remaining R1 and R2 substituents are hydrogen.
The invention further includes compounds where A is C-R3, i.e. compounds of Formula III 
and the pharmaceutically acceptable salts thereof, wherein n, R, R1, R2, R3, and Ar are as defined for Formula I.
Preferred compounds of Formula III are compounds wherein n is 1 (hereinafter compounds of Formula IIIa).
The invention is particularly directed to compounds and pharmaceutically acceptable salts of Formula III wherein
Ar is phenyl, pyridyl, pyrimidinyl, pyrazolyl, or pyridizinyl, each of which is unsubstituted or substituted with up to three groups independently selected from halogen, cyano, nitro, C1-C6haloalkyl, C1-C6haloalkoxy, hydroxy, amino, and C1-C6alkyl substituted with 0-2 RA, C1-C6alkoxy substituted with 0-2 RA, xe2x80x94NH(C1-C6alkyl) substituted with 0-2 RA, and xe2x80x94N(C1-C6alkyl)(C1-C6alkyl) where each alkyl is independently substituted with 0-2 RA, xe2x80x94XRB, and RC;
RA is independently selected at each occurrence the group consisting of halogen, hydroxy, C1-C6alkyl, C1-C6alkoxy, xe2x80x94NH(C1-C6alkyl), xe2x80x94N(C1-C6alkyl)(C1-C6alkyl), C1-C6haloalkyl, C1-C6haloalkoxy, xe2x80x94XRB and Y;
X is independently selected at each occurrence from the group consisting of xe2x80x94CH2xe2x80x94, xe2x80x94CHRCxe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94NRCxe2x80x94, and xe2x80x94C(xe2x95x90O)xe2x80x94;
RB and RC are independently C1-C6 alkyl, C3-C7cycloalkyl, or C3-C7cycloalkyl(C1-C6)alkyl, each of is optionally substituted with one or more substituents independently selected from oxo, hydroxy, halogen, amino, cyano, nitro, C1-C6 haloalkyl, C1-C6 -haloalkoxy, C1-C6 alkyl, C1-C6 alkoxy, mono- or di(C1-C6)alkylamino, xe2x80x94NHC(O)(C1-C6alkyl), and xe2x80x94N(C1-C6 alkyl)C(O)(C1-C6alkyl), where m is 0, 1, or 2; and
Y is morpholinyl, homopiperazinyl, piperazinyl, homo piperidinyl, piperidinyl, tetrahydropyridyl, imidazolyl, imidazolinyl, or imidazolidinyl.
More preferably Ar in Formula III is phenyl, pyridyl, or pyridizinyl each of which is optionally mono-, di-, or tri-substituted with substituents independently chosen from
halogen, C1-C6 alkyl, C1-C6 alkoxy, amino, mono- or di(C1-C6)alkylamino, C1-C6alkoxy(C1-C6)alkoxy, C1-C6 alkylamino(C1-C6)alkoxy, amino(C1-C6)alkoxy, di(C1-C6)alkylamino(C1-C6)alkoxy, C1-C6 alkoxy(C1-C6)alkylamino,
alkyl substituted with morpholinyl, homopiperazinyl, piperazinyl, homopiperidinyl, piperidinyl, tetrahydropyridyl, imidazolyl, imidazolinyl, or imidazolidinyl, or
C1-C6 alkoxy substituted with morpholinyl, homopiperazinyl, piperazinyl, homo piperidinyl, piperidinyl, tetrahydropyridyl, imidazolyl, imidazolinyl, or imidazolidinyl.
The invention is also directed to compounds of Formula III in which R, R1, R2, R3 and n are as defined for Formula III and Ar is phenyl, pyridyl, or pyridinzyl, each of which is substituted with one of
i) halogen, C1-C6 alkyl, C1-C6 alkoxy, mono- or di-(C1-C6)alkylamino, C1-C6alkoxy(C1-C6)alkoxy, mono or di-(C1-C6)alkylamino(C1-C6)alkoxy, or
ii) C1-C6 alkoxy substituted with morpholinyl, homopiperazinyl, piperazinyl, homopiperidinyl, piperidinyl, tetrahydropyridyl, imidazolyl, imidazolinyl, or imidazolidinyl and
Ar is optionally further substituted with one or two substitutuents independently chosen from:
halogen, C1-C4 alkyl, C1-C4 alkoxy, amino, C1-C6 alkylamino, C1-C3 alkoxy(C1-C3)alkoxy, C1-C3 alkylamino(C1-C3)alkoxy, amino(C1-C3)alkoxy, C1-C3 alkylamino(C1-C3)alkoxy, and C1-C6alkoxy(C1-C6)alkylamino.
Such compounds are referred to hereinafter as compounds of Formula IIIb.
Particularly preferred definitions for the variables R1 and R2 of Formula III include hydrogen, C1-C2 alkyl, C1-C2 alkoxy, cyano, amino, and halogen. It is also preferred that not more than three of R1 and R2 are other than hydrogen. More preferred compounds and salts of Formula III are those wherein one, two, or three of R1 and R2 are independently chosen from hydrogen, halogen, methyl and ethyl, and the remaining R1 and R2 substituents are hydrogen.
Other preferred compounds and pharmaceutically acceptable salts of the invention are those wherein
Ar is as defined for compounds of Formula IIIb;
n and R3 are as defined for Formula III;
R is C1-C6alkyl, C1-C6alkoxy, phenyl(C1-C6)alkyl, pyridyl(C1-C6)alkyl, phenyl or pyridyl, wherein each phenyl or pyridyl is unsubstituted or mono-, di-, or tri-substituted with halogen, cyano, nitro, halo(C1-C6)alkyl, halo(C1-C6)alkoxy, hydroxy, amino, C1-C6alkyl substituted with 0-2 RA, C1-C6alkoxy substituted with 0-2 RA, xe2x80x94NH(C1-6 alkyl) substituted with 0-2 RA, xe2x80x94N(C1-C6alkyl)(C1-C6alkyl) where each C1-C6alkyl is independently substituted with 0-2 RA, phenyl substituted with 0-3 RA, xe2x80x94XRB, and RC (X, RB, and RC are defined as for Formula III) and
one, two, or three of R1 and R2 are independently chosen from hydrogen, halogen, methyl and ethyl, and the remaining R1 and R2 substituents are hydrogen.
Such compounds are referred to as compounds of Formula IIIc.
Particularly preferred compounds and salts of Formula IIIc are those wherein
R is C1-6 alkyl, C1-6 alkoxy, or
phenyl(C1-C6)alkyl, pyridyl(C1-C6)alkyl, phenyl or pyridyl, wherein each phenyl or pyridyl is unsubstituted or mono-, di-, or trisubstituted with substitutents independently chosen from halogen, cyano, nitro, C1-C6haloalkyl, C1-C6haloalkoxy, hydroxy, amino, C1-C6 alkoxy, and C1-6 alkyl.
Other preferred compounds and pharmaceutically acceptable salts of Formula III are those wherein
Ar is phenyl, pyridyl, pyrimidinyl, pyrazolyl, or pyridizinyl, each of which is unsubstituted or substituted with up to three groups independently selected from: halogen, cyano, nitro, C1-C6haloalkyl, C1-C6haloalkoxy, hydroxy, amino, and C1-C6alkyl substituted with 0-2 RA, C1-C6alkoxy substituted with 0-2 RA, xe2x80x94NH(C1-C6alkyl) substituted with 0-2 RA, xe2x80x94N(C1-C6alkyl)(C1-C6alkyl) where each alkyl is independently substituted with 0-2 RA, xe2x80x94XRB, and RC;
RA is independently selected at each occurrence the group consisting of halogen, hydroxy, C1-C6alkyl, C1-C6alkoxy, xe2x80x94NH(C1-C6alkyl), xe2x80x94N(C1-C6alkyl)(C1-C6alkyl) C1-C6haloalkyl, C1-C6haloalkoxy, CO(C1-C6alkyl), CONH(C1-C6alkyl), CON(C1-C6alkyl)(C1-C6alkyl), xe2x80x94XRB and Y;
X is independently selected at each occurrence from the group consisting of xe2x80x94CH2xe2x80x94, xe2x80x94CHRCxe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94S(O)gxe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94NRCxe2x80x94, xe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94C(xe2x95x90O)Oxe2x80x94, xe2x80x94C(xe2x95x90O)NHxe2x80x94, xe2x80x94C(xe2x95x90O)NRCxe2x80x94, xe2x80x94S(O)gNHxe2x80x94, xe2x80x94S(O)gNRCxe2x80x94, NHC(xe2x95x90O)xe2x80x94, xe2x80x94NRCC(xe2x95x90O)xe2x80x94, xe2x80x94NHS(O)nxe2x80x94, and xe2x80x94NRCS(O)nxe2x80x94; where g is 0, 1, or 2;
RB and RC are independently alkyl groups which may be further substituted with one or more substituent(s) selected from oxo, hydroxy, halogen, amino, cyano, nitro, C1-C6haloalkyl, C1-C6haloalkoxy, xe2x80x94O(C1-C6alkyl), xe2x80x94NH(C1-6 alkyl), xe2x80x94N(C1-C6alkyl)(C1-6 alkyl), xe2x80x94NHC(O)(C1-C6alkyl), xe2x80x94N(alkyl)C(O)(C1-C6alkyl), xe2x80x94NHS(O)m(C1-C6alkyl), xe2x80x94S(O)m(C1-C6alkyl), xe2x80x94S(O)mNH(C1-C6alkyl), and xe2x80x94S(O)mN(C1-C6alkyl)(C1-C6alkyl); where m is 0, 1, or 2; and
Y is morpholinyl, homopiperazinyl, piperazinyl, homo piperidinyl, piperidinyl, tetrahydropyridyl, imidazolyl, imidazolinyl, or imidazolidinyl, each of which is unsubstituted or further substituted with one or more substituents independently chosen from halogen, oxo, hydroxy, amino, mono- or di(C1-C6)alkylamino, nitro, cyano, C1-C6 alkyl, C1-C6 alkoxy.
Such compounds are referred to hereinafter as compounds of Formula IIId.
Preferred compounds and pharmaceutically acceptable salts of Formula IIId are those wherein R is C1-C4alkyl, C1-C4alkoxy, or phenyl, where the phenyl is mono- or di-substituted with substituents independently chosen from halogen, cyano, nitro, C1-C6haloalkyl, C1-C6haloalkoxy, hydroxy, amino, C1-C6 alkoxy, C1-6 alkyl, amino(C1-C6)alkyl, mono- or di(C1-C6)alkylamino(C1-C6)alkyl, and mono- or di(C1-C6)alkylamino(C1-C6)alkoxy.
The invention specifically embraces compounds of Formulae IV, V, VI, VII, VIII, and IX. 
In each of Formulae IV-IX, Z1 and Z2 are independently CH or nitrogen, each R, R1 and R2 independently carries the same definition assigned with respect to Formula I, and R20 and R21 are independently hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, amino, mono- or di(C1-C6)alkylamino, C1-C6 alkoxy(C1-C6)alkoxy, C1-C6 alkylamino(C1-C6)alkoxy, amino(C1-C6)alkoxy, di(C1-C6)alkylamino(C1-C6)alkoxy, C1-C6 alkoxy(C1-C6)alkylamino, or (C5-C7) heterocycloalkyl (C1-C6)alkoxy. Preferred heterocycloalkyl groups in Formulae IV-IX are morpholinyl, piperidinyl, and piperazinyl.
Preferably one of R20 and R21 is hydrogen, C1-C2 alkyl, halogen, or C1-C2 alkoxy and the other is morpholinyl- or piperidinyl-(C2-C4)alkoxy, or mono- or di(C1-C3)alkylamino(C2-C4) alkoxy. More preferably, one of R20 and R21 is hydrogen or halogen and the other is mono- or di(C1-C3)alkylamino(C2-C3)alkoxy or morpholinyl- or piperidinyl-(C2-C4)alkoxy.
Preferred R groups in Formulae IV to IX include hydroxy and C1-C3 alkoxy. More preferred R groups are methoxy and ethoxy.
Particularly preferred compounds of Formulae IV to IX are those where one of R20 and R21 is hydrogen or halogen in the 2- or 3-position with respect to the point of attachment of the 6-membered aromatic ring to the amide nitrogen and the other is in the 3- or, more preferably, in the 4-position with respect to the point of attachment to the amide nitrogen.
In Formulae IV to IX, preferably one of Z1 and Z2 is CH and the other is CH or both of Z1 and Z2 are CH. More preferred compounds of IV to IX are those where both Z1 and Z2 are CH.
Preferably, R1 and R2 are independently selected at each occurrence from hydrogen, halogen, hydroxy, C1-6 alkyl, C1-6 alkoxy, trifluoromethyl, trifluoromethoxy, nitro, cyano, amino, mono- or di(C1-6)alkylamino. More preferably, R1 and R2 are independently selected at each occurrence from hydrogen, methyl and ethyl.
Preferred R groups in Formulae IV-IX are R is
C1-6 alkyl, C1-6 alkoxy, or
phenyl(C1-C6)alkyl, pyridyl(C1-C6)alkyl, phenyl or pyridyl, where the aromatic portion of each is unsubstituted or mono-, di-, or trisubstituted with halogen, cyano, nitro, trifluoromethyl, trifluoromethoxy, hydroxy, amino, C1-C6 alkoxy, or C1-6 alkyl.
This invention provides fused pyrroleoxime and pyrazoleoxime derivatives. Preferred examples of the invention bind with high affinity to the benzodiazepine site of GABAA receptors, including human GABAA receptors. Particularly preferred compounds are those that bind with high selectivity to the benzodiazepine site of GABAA receptors, including human GABAA receptors. Without wishing to be bound to any particular theory, it is believed that the interaction of the compounds of Formula I with the benzodiazepine site results in the pharmaceutical utility of these compounds.
The invention further comprises methods of treating patients in need of such treatment with an amount of a compound of the invention sufficient to alter the symptoms of a CNS disorder. Compounds of the inventions that act as agonists at xcex12xcex23xcex32 and xcex13xcex23xcex32 receptor subtypes are useful in treating anxiety disorders such as panic disorder, obsessive compulsive disorder and generalized anxiety disorder; stress disorders including post-traumatic stress, and acute stress disorders. Compounds of the inventions that act as agonists at xcex12xcex23xcex32 and xcex13xcex23xcex32 receptor subtypes are also useful in treating depressive or bipolar disorders and in treating sleep disorders. Compounds of the invention that act as inverse agonists at the xcex15xcex23xcex32 receptor subtype or xcex11xcex22xcex32 and xcex15xcex23xcex32 receptor subtypes are useful in treating cognitive disorders including those resulting from Down Syndrome, neurodegenerative diseases such as Alzheimer""s disease and Parkinson""s disease, and stroke related dementia. Compounds of the invention that act as agonists at the xcex11xcex22xcex32 receptor subtype are useful in treating convulsive disorders such as epilepsy. Compounds that act as antagonists at the benzodiazepine site are useful in reversing the effect of benzodiazepine overdose and in treating drug and alcohol addiction.
The diseases and/or disorders that can also be treated using compounds and compositions according to the invention include:
Depression, e.g. depression, atypical depression, bipolar disorder, depressed phase of bipolar disorder.
Anxiety, e.g. general anxiety disorder (GAD), agoraphobia, panic disorder +/xe2x88x92 agoraphobia, social phobia, specific phobia, Post traumatic stress disorder, obsessive compulsive disorder (OCD), dysthymia, adjustment disorders with disturbance of mood and anxiety, separation anxiety disorder, anticipatory anxiety acute stress disorder, adjustment disorders, cyclothymia.
Sleep disorders, e.g. sleep disorders including primary insomnia, circadian rhythm sleep disorder, dyssomnia NOS, parasomnias, including nightmare disorder, sleep terror disorder, sleep disorders secondary to depression and/or anxiety or other mental disorders, substance induced sleep disorder.
Cognition Impairment, e.g. cognition impairment, Alzheimer""s disease, Parkinson""s disease, mild cognitive impairment (MCI), age-related cognitive decline (ARCD), stroke, traumatic brain injury, AIDS associated dementia, and dementia associated with depression, anxiety or psychosis.
Attention Deficit Disorder, e.g. attention deficit disorder (ADD), and attention deficit and hyperactivity disorder (ADHD).
The invention also provides pharmaceutical compositions comprising compounds of the invention, including packaged pharmaceutical compositions for treating disorders responsive to GABAA receptor modulation, e.g., treatment of anxiety, depression, sleep disorders or cognitive impairment by GABAA receptor modulation. The packaged pharmaceutical compositions include a container holding a therapeutically effective amount of at least one GABAA receptor modulator as described supra and instructions (e.g., labeling) indicating the contained GABAA receptor ligand is to be used for treating a disorder responsive to GABAA receptor modulation in the patient.
In a separate aspect, the invention provides a method of potentiating the actions of other CNS active compounds, which comprises administering an effective amount of a compound of the invention in combination with another CNS active compound. Such CNS active compounds include, but are not limited to the following: for anxiety, serotonin receptor (e.g. 5-HT1A) agonists and antagonists; for anxiety and depression, neurokinin receptor antagonists or corticotropin releasing factor receptor (CRF1) antagonists; for sleep disorders, melatonin receptor agonists; and for neurodegenerative disorders, such as Alzheimer""s dementia, nicotinic agonists, muscarinic agents, acetylcholinesterase inhibitors and dopamine receptor agonists. Particularly the invention provides a method of potentiating the antidepressant activity of selective serotonin reuptake inhibitors (SSRIs) by administering an effective amount of a GABA agonist compound of the invention in combination with an SSRI.
Combination administration can be carried out in a fashion analogous to that disclosed in Da-Rocha, et al., J. Psychopharmacology (1997) 11(3) 211-218; Smith, et al., Am. J. Psychiatry (1998) 155(10) 1339-45; or Le, et al., Alcohol and Alcoholism (1996) 31 Suppl. 127-132. Also see, the discussion of the use of the GABAA receptor ligand 3-(5-methylisoxazol-3-yl)-6-(1-methyl-1,2,3-triazol-4-yl) methyloxy-1,2,4-triazolo [3,4-a]phthalazine in combination with nicotinic agonists, muscarinic agonists, and acetylcholinesterase inhibitors, in PCT International publications Nos. WO 99/47142, WO 99/47171, and WO 99/47131, respectively. Also see in this regard PCT International publication No. WO 99/37303 for its discussion of the use of a class of GABAA receptor ligands, 1,2,4-triazolo[4,3-b]pyridazines, in combination with SSRIs.
The invention also pertains to methods of inhibiting the binding of benzodiazepine compounds, such as Ro15-1788, to the GABAA receptors which methods involve contacting a compound of the invention with cells expressing GABAA receptors, wherein the compound is present at a concentration sufficient to inhibit benzodiazepine binding to GABAA receptors in vitro. This method includes inhibiting the binding of benzodiazepine compounds to GABAA receptors in vivo, e.g., in a patient given an amount of a compound of Formula I that would be sufficient to inhibit the binding of benzodiazepine compounds to GABAA receptors in vitro. In one embodiment, such methods are useful in treating benzodiazepine drug overdose. The amount of a compound that would be sufficient to inhibit the binding of a benzodiazepine compound to the GABAA receptor may be readily determined via an GABAA receptor binding assay, such as the assay described in Example 5. The GABAA receptors used to determine in vitro binding may be obtained from a variety of sources, for example from preparations of rat cortex or from cells expressing cloned human GABAA receptors.
The invention also pertains to methods for altering the signal-transducing activity, particularly the chloride ion conductance of GABAA receptors, said method comprising exposing cells expressing such receptors to an effective amount of a compound of the invention. This method includes altering the signal-transducing activity of GABAA receptors in vivo, e.g., in a patient given an amount of a compound of Formula I that would be sufficient to alter the signal-transducing activity of GABAA receptors in vitro. The amount of a compound that would be sufficient to alter the signal-transducing activity of GABAA receptors may be determined via a GABAA receptor signal transduction assay, such as the assay described in Example 6.
The GABAA receptor ligands provided by this invention and labeled derivatives thereof are also useful as standards and reagents in determining the ability of a potential pharmaceutical to bind to the GABAA receptor.
Labeled derivatives of the GABAA receptor ligands provided by this invention are also useful as radiotracers for positron emission tomography (PET) imaging or for single photon emission computerized tomography (SPECT).
The compounds herein described may have one or more asymmetric centers. Compounds of the invention containing an asymmetrically substituted atom may be isolated in enantiomerically enriched or racemic form. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms (racemates), by asymmetric synthesis, or by synthesis from optically active starting materials. Resolution of the racemates can be accomplished, for example, by conventional methods such as crystallization in the presence of a resolving agent; derivatizing with an enantiomerically enriched resolving reagent, separating the resulting diastereomers through means well known in the art, and removing the enantiomerically enriched resolving reagent through ordinary chemical means such as, for example, hydrolysis or hydrogenation; or chromatography, using, for example a chiral HPLC column.
Many geometric isomers of olefins, carbon-nitrogen double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the invention. Cis and trans geometric isomers, as well as E and Z isomers of the compounds of the invention are described and may be isolated as a mixture of isomers or as separated isomeric forms. All chiral (enantiomeric and diastereomeric), and racemic forms, as well as all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomeric form is specifically indicated.
Some compounds of the invention exist as tautomers. Unless otherwise specified, any description or claim of one tautomeric form is intended to encompass the other tautomer.
The term xe2x80x9csubstitutedxe2x80x9d, as used herein, means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom""s normal valence is not exceeded, and that the substitution results in a stable compound. When a substituent is keto (i.e., xe2x95x90O), then 2 hydrogens on the atom are replaced. Unless otherwise specified, when a group is substituted with more than one substituent, it is understood that the substituents are the same or different.
The invention includes all isotopes of atoms occurring in the compounds. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium. Isotopes of carbon include 11C, 13C, and 14C.
When any variable occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-2 R*, then said group may optionally be substituted with up to two R* groups and each R* is selected independently from the definition of R*. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds. Also, for example, dialkylamino groups are understood to contain two alkyl, preferably C1-C6 alkyl, groups that may be the same or different. Thus, dialkylamino encompasses N-ethyl-N-methylamino, N, N-diethylamino, N,N-dimethylamino, N-methyl-N-propylamino, and the like.
Where the term xe2x80x9calkylxe2x80x9d is used, either alone or within other terms such as xe2x80x9chaloalkylxe2x80x9d and xe2x80x9calkylsulfonylxe2x80x9d, it embraces linear and branched radicals having one to about twelve carbon atoms. Preferred alkyl radicals are xe2x80x9clower alkylxe2x80x9d radicals having one to about ten carbon atoms. More preferred are lower alkyl radicals having one to about six carbon atoms. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, and sec-pentyl and the like. Preferred alkyl groups are C1-C6 alkyl groups. Especially preferred alkyl groups are methyl, ethyl, propyl, butyl, 3-pentyl. The term C1-C6 alkyl as used herein includes alkyl groups having from 1 to 6 carbon atoms. Preferred examples are methyl and ethyl.
xe2x80x9cAlkylsulfonylxe2x80x9d embraces alkyl groups attached to a sulfonyl radical, where alkyl is defined as above, i.e., a group of the formula xe2x80x94SOa(alkyl). More preferred alkylsulfonyl radicals are xe2x80x9clower alkylsulfonylxe2x80x9d radicals having one to six carbon atoms. Examples of such lower alkylsulfonyl radicals include methylsulfonyl, ethylsulfonyl and propylsulfonyl.
The term xe2x80x9calkylsulfinylxe2x80x9d embraces radicals containing a linear or branched alkyl radical, of one to ten carbon atoms, attached to a divalent xe2x80x94S(xe2x95x90O)xe2x80x94atom.
The terms xe2x80x9cN-alkylaminoxe2x80x9d and xe2x80x9cN,N-dialkylaminoxe2x80x9d denote amino groups which have been substituted with one alkyl radical and with two alkyl radicals, respectively. More preferred alkylamino radicals are xe2x80x9clower alkylaminoxe2x80x9d radicals having one or two alkyl radicals of one to six carbon atoms, attached to a nitrogen atom. Suitable xe2x80x9calkylaminoxe2x80x9d may be mono or dialkylamino such as N-methylamino, N-ethylamino, N,N-dimethylamino, N,N-diethylamino or the like.
The term xe2x80x9calkylthioxe2x80x9d embraces groups containing a linear or branched alkyl radical, of one to ten carbon atoms, attached to a divalent sulfur atom. An example of xe2x80x9calkylthioxe2x80x9d is methylthio, (CH3xe2x80x94Sxe2x80x94).
The term xe2x80x9ccycloalkylxe2x80x9d embraces radicals having three to ten carbon atoms. More preferred cycloalkyl radicals are xe2x80x9clower cycloalkylxe2x80x9d radicals having three to seven carbon atoms, i.e., C3-C7 cycloalkyl. Examples include radicals such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
In the term xe2x80x9cC3-C7 cycloalkylalkylxe2x80x9d, the C3-7 cycloalkyl group is attached to the parent molecular moiety through the alkyl, preferably a C1-C6, more preferably a C1-C4 alkyl, group. This term encompasses, but is not limited to, cyclopropylmethyl, and cyclohexylmethyl.
By xe2x80x9ccarboxamidoxe2x80x9d as used herein is meant groups of the formula xe2x80x94C(O)NRxe2x80x2Rxe2x80x3 where Rxe2x80x2 and Rxe2x80x3 are the same or different and represent hydrogen or alkyl. Preferred carboxamido groups are those where both of Rxe2x80x2 and Rxe2x80x3 are hydrogen.
The term xe2x80x9calkenylxe2x80x9d embraces unsaturated straight and branched chain radicals having two to about ten carbon atoms. Such radicals contain at least one carbon-carbon double bond which may occur at any stable point along the chain. Examples of alkenyl groups include, but are not limited to such groups as ethenyl and propenyl.
The term xe2x80x9calkynylxe2x80x9d embraces straight and branched chain radicals having two to about ten carbon atoms and at least one carbon-carbon triple bond. The carbon-carbon triple bond may occur at any stable point along the chain. Examples of alkynyl groups include, but are not limited to such groups as ethynyl and propynyl.
xe2x80x9cAlkoxyxe2x80x9d represents an alkyl group as defined above attached to the parent molecular moiety through an oxygen bridge. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, 2-butoxy, tert-butoxy, n-pentoxy, 2-pentoxy, 3-pentoxy, isopentoxy, neopentoxy, n-hexoxy, 2-hexoxy, 3-hexoxy, and 3-methylpentoxy. More preferred alkoxy groups include methoxy, ethoxy, isopropoxy, and isobutoxy.
As used herein, xe2x80x9calkanoylxe2x80x9d refers to an alkyl group as defined above attached through a carbonyl bridge, i.e., xe2x80x94CO(alkyl). Examples include acetyl, propionyl, and butyryl.
The term xe2x80x9carylxe2x80x9d is used to indicate aromatic groups that contain only carbon atoms in the ring structure. Thus, the term xe2x80x9carylxe2x80x9d refers to an aromatic hydrocarbon ring system containing at least one aromatic ring. The aromatic ring may optionally be fused or otherwise attached to other aromatic hydrocarbon rings or non-aromatic hydrocarbon rings. Examples of aryl groups are, for example, phenyl, naphthyl, 1,2,3,4-tetrahydronaphthalene, indanyl, and biphenyl. Preferred aryl groups include phenyl, naphthyl, including 1-naphthyl and 2-naphthyl, and acenaphthyl. More preferred aryl groups include phenyl and napthyl. The aryl groups herein are unsubstituted or, as specified, substituted in one or more substitutable positions with various groups. Thus, such aryl groups are optionally substituted with, for example, C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxy, cyano, nitro, amino, mono- or di-(C1-C6)alkylamino, C2-C6alkenyl, C2-C6alkynyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, amino(C1-C6)alkyl, mono- or di(C1-C6)alkylamino(C1-C6)alkyl.
The term xe2x80x9chaloalkylxe2x80x9d is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with 1 or more halogen (for example xe2x80x94CvFw where v=1 to 3 and w=1 to (2v+1). Examples of haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl. Preferred haloalkyl groups are halo(C1-C6)alkyl groups; particularly preferred are trifluoromethyl, perfluoropropyl, and difluoromethyl.
By xe2x80x9chaloalkoxyxe2x80x9d as used herein is meant represents a haloalkyl group, as defined above, attached through an oxygen bridge to a parent group. Preferred haloalkoxy groups are halo(C1-C6)alkoxy groups. Examples of haloalkoxy groups are trifluoromethoxy, 2,2-difluoroethoxy, 2,2,3-trifluoropropoxy and perfluoroisopropoxy.
Where the term xe2x80x9chydrocarbylxe2x80x9d is used, either alone or within other terms such as xe2x80x9chydrocarbylthioxe2x80x9d and xe2x80x9chydrocarbylsulfinylxe2x80x9d, it embraces straight, branched, and cyclic hydrocarbon groups having from 1 to about 12 carbon atoms. The hydrocarbyl groups are saturated or unsaturated, i.e., they contain one or more carbon-carbon double or triple bonds. Examples of hydrocarbyl groups include, for example, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, 3-methylpentyl, vinyl, isobutenyl, 2-pentenyl, 3-undecenyl, 4-nonenyl, acetylenyl, 2-methyl-pent-3-ynyl, 1-methyl-hex-2-ynyl, cyclopropylmethyl, cyclopropyl, cyclohexylmethyl, cyclohexyl and propargyl. When reference is made herein to C1-C6 hydrocarbyl containing one or two double or triple bonds it is understood that at least two carbons are present in the group for one double or triple bond, and at least four carbons for two double or triple bonds.
As used herein, the term xe2x80x9cheteroarylxe2x80x9d means stable monocyclic, bicylclic and tricyclic ring systems which contain at least one aromatic ring where the aromatic ring contains from 5-7 members and from 1 to 4 hetero atoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; the remaining rings contain from 5-7 members selected from carbon, oxygen, nitrogen, and sulfur. The aromatic ring containing a hetero atom is the xe2x80x9cheteroaromatic ring.xe2x80x9d In bicyclic and tricyclic ring systems, the heteroaromatic ring may be fused to a carbocyclic ring that may be aromatic, such as benzo, or to a heteroaromatic ring, such as pyrido or pyrrolidino, or to heteroaromatic and one carbocyclic ring. Thus, xe2x80x9cheteroarylxe2x80x9d includes ring systems having from one to three rings of from 5-7 ring members in each ring and where at least one ring is aromatic and contains from one to four hetero atoms. Any of the rings in the heteroaryl groups may be further fused to another ring forming a spiro ring system.
The nitrogen and sulfur heteroatoms may optionally be oxidized. The heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom which results in a stable structure. The heterocyclic rings described herein may be substituted on any substitutable carbon or nitrogen atom that results in a stable compound. Examples of suitable heteraryl substituents are C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxy, cyano, nitro, amino, mono- or di-(C1-C6)alkylamino, C2-C6alkenyl, C2-C6alkynyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, amino(C1-C6)alkyl, and mono- or di(C1-C6)alkylamino(C1-C6)alkyl.
Examples of heteroaryl groups include, but are not limited to, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, NH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl; 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl.
Preferred heteroaryl groups include, but are not limited to, pyridinyl, pyrimidinyl, furanyl, and thienyl.
As used herein, the term xe2x80x9cheterocycloalkylxe2x80x9d is intended to mean a stable 5- to 7-membered monocyclic or 7- to 10-membered bicyclic ring system which contains at least one non-aromatic ring wherein said ring consists of carbon atoms and from 1 to 4 heteroatoms independently selected from the group consisting of N, 0 and S. The heterocycloalkyl ring or heterocycloalkyl bicyclic ring system may be fused to a benzene ring. A nitrogen in the heterocycle may optionally be quaternized. It is preferred that when the total number of S and 0 atoms in the heterocycloalkyl group exceeds 1, then these heteroatoms are not adjacent to one another. It is also preferred that the total number of S and 0 atoms in the heterocycloalkyl is not more than 1. Examples of heterocycloalkyl groups include but are not limited to tetrahydroquinolinyl, tetrahydroisoquinolinyl, pyrrolyl, piperazinyl, piperidinyl, tetrahydrofuranyl, morpholinyl, azetidinyl, 2H-pyrrolyl.
The term xe2x80x9chalogenxe2x80x9d indicates fluorine, chlorine, bromine, and iodine.
The term xe2x80x9cxe2x80x94Oxe2x80x94xe2x80x9d represents an oxygen linker. Thus, the terms xe2x80x9cxe2x80x94O-arylxe2x80x9d and xe2x80x9cxe2x80x94O-heteroarylxe2x80x9d refer to aryl and heteroaryl groups as defined above connected though an oxygen atom to a parent molecular group. The terms xe2x80x9caryloxyxe2x80x9d and xe2x80x9cxe2x80x94O-arylxe2x80x9d are equivalent as used herein. In addition, the terms xe2x80x9cheteroaryloxyxe2x80x9d and xe2x80x9cxe2x80x94O-heteroarylxe2x80x9d are equivalent as used herein.
Non-toxic pharmaceutically acceptable salts include, but are not limited to salts of inorganic acids such as hydrochloric, sulfuric, phosphoric, diphosphoric, hydrobromic, and nitric or salts of organic acids such as formic, citric, malic, maleic, fumaric, tartaric, succinic, acetic, lactic, methanesulfonic, p-toluenesulfonic, 2-hydroxyethylsulfonic, salicylic and stearic. Similarly, pharmaceutically acceptable cations include, but are not limited to sodium, potassium, calcium, aluminum, lithium and ammonium. Those skilled in the art will recognize a wide variety of non-toxic pharmaceutically acceptable addition salts. The invention also encompasses prodrugs of the compounds of Formula I.
The invention also encompasses the acylated prodrugs of the compounds of Formula I. Those skilled in the art will recognize various synthetic methodologies, which may be employed to prepare non-toxic pharmaceutically acceptable addition salts and acylated prodrugs of the compounds encompassed by Formula I.
Pharmaceutical Preparations
Those skilled in the art will recognize various synthetic methodologies that may be employed to prepare non-toxic pharmaceutically acceptable prodrugs of the compounds encompassed by Formula I. Those skilled in the art will also recognize a wide variety of non-toxic pharmaceutically acceptable solvents that may be used to prepare solvates of the compounds of the invention, such as water, ethanol, mineral oil, vegetable oil, and dimethylsulfoxide.
The compounds of general Formula I may be administered orally, topically, parenterally, by inhalation or spray or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. Oral administration in the form of a pill, capsule, elixir, syrup, lozenge, troche, or the like is particularly preferred. The term parenteral as used herein includes subcutaneous injections, intradermal, intravascular (e.g., intravenous), intramuscular, spinal, intrathecal injection or like injection or infusion techniques. In addition, there is provided a pharmaceutical formulation comprising a compound of general Formula I and a pharmaceutically acceptable carrier. One or more compounds of general Formula I may be present in association with one or more non-toxic pharmaceutically acceptable carriers and/or diluents and/or adjuvants and if desired other active ingredients. The pharmaceutical compositions containing compounds of general Formula I may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsion, hard or soft capsules, or syrups or elixirs.
Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients that are suitable for the manufacture of tablets. These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed.
Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.
Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydropropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example, lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.
Oily suspensions may be formulated by suspending the active ingredients in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide palatable oral preparations. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.
Pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol, anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavoring agents.
Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents. The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be sterile injectable solution or suspension in a non-toxic parentally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer""s solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.
The compounds of general Formula I may also be administered in the form of suppositories, e.g., for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols.
Compounds of general Formula I may be administered parenterally in a sterile medium. The drug, depending on the vehicle and concentration used, can either be suspended or dissolved in the vehicle. Advantageously, adjuvants such as local anesthetics, preservatives and buffering agents can be dissolved in the vehicle.
For administration to non-human animals, the composition may also be added to the animal feed or drinking water. It may be convenient to formulate these animal feed and drinking water compositions so that the animal ingests an appropriate quantity of the composition during a meal or throughout the course of the day. It may also be convenient to present the composition as a premix for addition to the feed or drinking water.
Dosage levels of the order of from about 0.1 mg to about 140 mg per kilogram of body weight per day are useful in the treatment of the above-indicated conditions (about 0.5 mg to about 7 g per patient per day). The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. Dosage unit forms will generally contain between from about 1 mg to about 500 mg of an active ingredient.
Frequency of dosage may also vary depending on the compound used and the particular disease treated. However, for treatment of most disorders, a dosage regimen of 4 times daily or less is preferred. For the treatment of anxiety, depression, or cognitive impairment a dosage regimen of 1 or 2 times daily is particularly preferred. For the treatment of sleep disorders a single dose that rapidly reaches effective concentrations is desirable.
It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combination and the severity of the particular disease undergoing therapy.
Preferred compounds of the invention will have pharmacological properties that include, but are not limited to oral bioavailability, low toxicity, low serum protein binding and desirable in vitro and in vivo half-lives. Penetration of the blood brain barrier for compounds used to treat CNS disorders is necessary, while low brain levels of compounds used to treat peripheral disorders are often preferred.
Assays may be used to predict these desirable pharmacological properties. Assays used to predict bioavailability include transport across human intestinal cell monolayers, including Caco-2 cell monolayers. Toxicity to cultured hepatocytes may be used to predict compound toxicity. Penetration of the blood brain barrier of a compound in humans may be predicted from the brain levels of the compound in laboratory animals given the compound intravenously.
Serum protein binding may be predicted from albumin binding assays. Such assays are described in a review by Oravcovxc3xa1, et al. (Journal of Chromatography B (1996) volume 677, pages 1-27).
Compound half-life is inversely proportional to the frequency of dosage of a compound. In vitro half-lives of compounds may be predicted from assays of microsomal half-life as described by Kuhnz and Gieschen (Drug Metabolism and Disposition, (1998) volume 26, pages 1120-1127).
Preparation of Compounds
A general illustration of the preparation of compounds of Formula I in the invention is given in Scheme I. 
R, R1, R2, n, A and Ar are as defined in claim 1.
With respect to the preparation of the oximes of the invention (Scheme I), an appropriately substituted amine (RNH2) is added to a suspension of the pyrrole or pyrazole carboxamide starting material in ethanol or other suitable solvent. The reaction mixture is heated for approximately 16 hours and the solvent is removed in vacuo to yield the oxime product (formula I).
The preparation of pyrrole carboxamides (formula A where Axe2x95x90CR3) can be accomplished according to the procedures set forth in U.S. Pat. No. 5,804,686, which is hereby incorporated by reference. Suitable procedures are also described in U.S. patent application Ser. No. 09/387,311, filed Aug. 31, 1999, and U.S. patent application Ser. No. 09/651,207, filed Aug. 30, 2000, the disclosures of which are incorporated herein in their entirety. The preparation of such compounds is generally depicted in Scheme II. Also, see International Applications WO 97/2624 and WO 01/16103.
The preparation of pyrazole carboxamides (Formula A where A is nitrogen) can be accomplished according to the procedures set forth in International Application WO 00/40565. 
The preparation of representative Arxe2x80x94NH2 groups is depicted below in Schemes III (1), (2) and (3). 
In Schemes III (1) and (2), R9 and R14 represent hydrogen or alkyl, preferably hydrogen or C1-C6 alkyl. In Scheme III(3), R18 and R19 independently represent hydrogen or alkyl, preferably hydrogen or C1-C6 alkyl, or NR18R19 represents a heterocycloalkyl group such as morpholinyl, piperidinyl, or piperazinyl.
The preparation of representative substituted pyridylamines useful as Arxe2x80x94NH2 groups for preparing compounds of Formula I as shown in Scheme II is depicted below in Scheme IV. In Scheme IV, R30 represents hydrogen or hydrocarbyl substituted with up to two RA groups, preferably hydrogen or alkyl substituted with up to two RA groups. 
The preparation of other representative substituted anilines useful as Arxe2x80x94NH2 groups for preparing compounds of Formula I as shown in Scheme II is depicted below in Scheme V. In Scheme V, R35 represents hydrogen or C1-C6 alkyl, preferably ethyl. 
Those skilled in the art will recognize that it may be necessary to utilize different solvents or reagents to achieve some of the above transformations. Unless otherwise specified all reagents and solvent are of standard commercial grade and are used without further purification.
The disclosures in this application of all articles and references, including patents, are incorporated herein by reference in their entirety.
The invention is illustrated further by the following examples, which are not to be construed as limiting the invention in scope or spirit to the specific procedures described in them. Those having skill in the art will recognize that the starting materials may be varied and additional steps employed to produce compounds encompassed by the invention, as demonstrated by the following examples. In some cases, protection of reactive functionalities may be necessary to achieve some of the above transformations. In general, such need for protecting groups, as well as the conditions necessary to attach and remove such groups, will be apparent to those skilled in the art of organic synthesis.